C2-disubstituted indan-1-ones and their derivatives, processes for their preparation and their use as pharmaceuticals

ABSTRACT

The present invention is directed C2-disubstituted indan-1-ones of the Formula I,  
                 
 
     physiologically acceptable salts, and physiologically functional derivatives thereof, and pharmaceutical compositions comprising such compounds, salts and derivatives, which are useful for reducing weight, for the prophylaxis or treatment of obesity, and for the prophylaxis or treatment of type II diabetes in mammals. The invention is directed also to methods for reducing weight and such treatments and prophylaxis. The invention is directed also to processes for the preparation of such compounds.

FIELD OF THE INVENTION

[0001] The invention relates to C2-disubstituted indan-1-ones and theirderivatives and also their physiologically acceptable salts andphysiologically functional derivatives.

BACKGROUND OF THE INVENTION

[0002] In F. C. Copp et al., J. Chem. Soc. Perkin I, 1983, 909-914, inthe preparation of 2-phenylindan-1-one, 2-phenyl-2-phenylthioindan-1-oneis obtained as an intermediate.

[0003] WO 97/20806 discloses cyclopentyl-substituted indan-1-onederivatives having inter alia antiinflammatory action.

[0004] WO 98/55439 discloses indan-1-one derivatives which aredisubstituted at C2 and have antiinflammatory action.

SUMMARY OF THE INVENTION

[0005] It is an object of the present invention to provide compoundswhich cause a reduction in weight in mammals and which are suitable forpreventing and treating obesity.

DETAILED DESCRIPTION OF THE INVENTION

[0006] Accordingly, the invention relates to compounds of the formula(I)

[0007] in which

[0008] R1, R2, R3, R4 independently of one another are H, F, Cl, Br, I,CN; N₃, NO₂, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CH₂-phenyl,O-phenyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl,S(O)₀₋₂(C₁-C₈)-alkyl, S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl,NH—(C₃-C₈)-cycloalkyl, N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂,NH—CO—(C₁-C₈)-alkyl, NH—CO—(C₃-C₈)-cycloalkyl; SO₃H, SO₂—NH₂,SO2-NH—(C₁-C₈)-alkyl, SO₂—NH—(C₃-C₈)-cycloalkyl, NH—SO₂—NH₂,NH—SO₂—(C₁-C₈)-alkyl, NH—SO₂—(C₃-C₈)-cycloalkyl, O—CH₂—COOH,O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O(C₁-C₈)-alkyl,CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂, (C₁-C₈)-alkyl, (C₃-C₈)cycloalkyl, (C₂-C₈)-alkenyl,(C₂-C₈)-alkynyl, wherein on the alkyl, alkenyl and alkynyl groups, ineach case, one to seven hydrogen atoms may be replaced by fluorine, orone hydrogen may be replaced by OH, OC(O)CH₃, O—CH₂-Ph, NH₂, NH—CO—CH₃or N(COOCH₂Ph)₂;

[0009] an aryl radical wherein the aryl radical is phenyl, or 1- or2-naphthyl; or

[0010] a heterocycle wherein the heterocycle is 5-tetrazolyl,1-[(C₁-C₆)-alkyl]-5-tetrazolyl, 2-[(C₁-C₆)-alkyl]-5-tetrazolyl,

[0011] 1-imidazolyl,

[0012] 1- or 4-[1,2,4]-triazolyl,

[0013] 2- or 3-thienyl,

[0014] 2- or 3-furyl,

[0015] 2-, 3- or 4-pyridyl,

[0016] 2-, 4- or 5-oxazolyl,

[0017] 3-, 4- or 5-isoxazolyl,

[0018] 2-, 4- or 5-thiazolyl, or

[0019] 3-, 4- or 5-isothiazolyl,

[0020] where the aryl radical or heterocycle may be substituted up totwo times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl,S(O)₀₋₂(C₁-C₆)-alkyl, NH₂, NH—SO₂—(C₁-C₄)-alkyl, COOH,CO—O—(C₁-C₄)-alkyl, or CO—NH₂, and wherein on the alkyl groups, one toseven hydrogen atoms may be replaced by fluorine;

[0021] X is S, SO, or SO₂;

[0022] Y is (CH₂)_(p), where p may be 0, 1, 2 or 3;

[0023] R5 is CF₃, (C₁-C₁₈)-alkyl, (C₃-C₄)-cycloalkyl, or(C₆-C₈)-cycloalkyl, wherein, on the alkyl groups, one to seven hydrogenatoms may be replaced by fluorine; or R5 is

[0024] (CH₂)_(r)—COR6, where r=1-6 and R6 may be OH, O—(C₁-C₆)-alkyl orNH₂; or R5 is

[0025] CH₂—CH(NHR7)-COR8, where R7 may be H or C(O)—(C₁-C₄)-alkyl and R8may be OH, O—(C₁-C₆)-alkyl or NH₂; or R5 is

[0026] Phenyl, 1- or 2-naphthyl, biphenyl or a heterocyclic radical,where the rings or ring systems of the phenyl, 1- or 2-naphthyl orheterocyclic radical may be substituted up to two times by F, Cl, Br, I,CN, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl,O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl,N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₂-C₈)-alkyl,NH—CO—(C₃-C₈)-cycloalkyl; SO₃H, SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,SO₂—NH—(C₃-C₈)-cycloalkyl; NH—SO₂—NH₂, NH—SO₂—(C₁-C₈)-alkyl,NH—SO₂—(C₃-C₈)-cycloalkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH,CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂, (C₁-C₈)-alkyl, or (C₃-C₈)-cycloalkyl, wherein onthe alkyl groups, in each case, one to seven hydrogen atoms may bereplaced by fluorine;

[0027] R9 is F, Cl, Br, CN, CF₃, (C₁-C₁₈)-alkyl, (C₃-C₄)-cycloalkyl, or(C₆-C₈)-cycloalkyl, wherein, on the alkyl groups, one to seven hydrogenatoms may be replaced by fluorine; or R9 is

[0028] (CH₂)_(r)—COR6, where r=9-16 and R6 may be OH, O—(C₁-C₆)-alkyl orNH₂; or R9 is

[0029] CH₂—CH(NHR7)-COR8 where R7 may be H or C(O)—(C₁-C₄)-alkyl and R8may be OH, O—(C₁-C₆)-alkyl or NH₂; or R9 is

[0030] (CH₂)_(u)-aryl or (CH₂)_(u)-heteroaryl, where u is 0 to 6 andaryl may be phenyl, 1- or 2-napthyl, biphenyl or a heterocyclic radical,where the rings or ring systems of aryl, heteroaryl or the heterocyclicradical may be substituted up to two times by F, Cl, Br, I, CN, OH,O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl,O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl,N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₂-C₈)-alkyl,NH—CO—(C₃-C₈)-cycloalkyl; SO₃H, SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,SO₂—NH—(C₃-C₈)-cycloalkyl; NH—SO₂—NH₂, NH—SO₂—(C₁-C₈)-alkyl,NH—SO₂—(C₃-C₈)-cycloalkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH,CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂, (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, wherein on thealkyl groups, in each case, one to seven hydrogen atoms may be replacedby fluorine;

[0031] and their physiologically acceptable salts;

[0032] provided that when R1, R2, R3 and R4 are all hydrogen, and X—Y—R5is S-phenyl, then R9 is other than phenyl.

[0033] Preference is given to compounds of the formula I in which

[0034] R1, R2, R3, R4 independently of one another are H, F, Cl, Br, CN;N₃, NO₂, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CH₂-phenyl,O-phenyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl, NH₂,NH—(C₁-C₈)-alkyl, N[(C₁-C₈)-alkyl]₂, COOH, CO—O(C₁-C₈)-alkyl,(C₁-C₈)-alkyl, (C₃-C₈)cycloalkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,wherein, on the alkyl, alkenyl and alkynyl groups, in each case, one toseven hydrogen atoms may be replaced by fluorine;

[0035] an aryl radical wherein the aryl radical is phenyl, or aheterocycle wherein the heterocycle is 1-imidazolyl,

[0036] where the aryl radical or heterocycle may be substituted up totwo times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, andwherein, on the alkyl groups, one to seven hydrogen atoms may bereplaced by fluorine;

[0037] X is S, SO, SO₂;

[0038] Y is (CH₂)_(p), where p may be 0, 1, 2 or 3;

[0039] R5 is CF₃, or (C₁-C₁₈)-alkyl, wherein, on the alkyl groups one toseven hydrogen atoms may be replaced by fluorine; or R5 is

[0040] (CH₂)_(r)—COR6, where r is 1 to 6 and R6 may be OH,O—(C₁-C₆)-alkyl or NH₂; or R5 is

[0041] CH₂—CH(NHR7)-COR8, where R7 may be H or C(O)—(C₁-C₄)-alkyl and R8may be OH, O—(C₁-C₆)-alkyl or NH₂; or R5 is

[0042] Phenyl, 1- or 2-naphthyl, biphenyl or a heterocyclic radical,where the rings or ring systems may be substituted up to two times by F,Cl, Br, I, CN, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl,O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl,N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₂-C₈)-alkyl,NH—CO—(C₃-C₈)-cycloalkyl; SO₃H, SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,SO₂—NH—(C₃-C₈)-cycloalkyl; NH—SO₂—NH₂, NH—SO₂—(C₁-C₈)-alkyl,NH—SO₂—(C₃-C₈)-cycloalkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH,CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂, (C₁-C₈)-alkyl, or (C₃-C₈)-cycloalkyl, wherein, onthe alkyl groups, in each case, one to seven hydrogen atoms may bereplaced by fluorine;

[0043] R9 is F, Cl, Br, CN, CF₃, (C₁-C₁₈)-alkyl, (C₃-C₄)-cycloalkyl, or(C₆-C₈)-cycloalkyl, wherein, on the alkyl groups, one to seven hydrogenatoms may be replaced by fluorine; or R9 is

[0044] (CH₂)_(u)-aryl or (CH₂)_(u)-heteroaryl, where u is 0 to 6 andaryl may be phenyl, 1- or 2-napthyl, biphenyl or a heterocyclic radical,where the rings or ring systems of aryl, heteroaryl, or the heterocyclicradical may be substituted up to two times by F, Cl, Br, I, CN, OH,O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl,O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl,N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₂-C₈)-alkyl,NH—CO—(C₃-C₈)-cycloalkyl; SO₃H, SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,SO₂—NH—(C₃-C₈)-cycloalkyl; NH—SO₂—NH₂, NH—SO₂—(C₁-C₈)-alkyl,NH—SO₂—(C₃-C₈)-cycloalkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH,CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂, (C₁-C₈)-alkyl, or (C₃-C₈)-cycloalkyl, wherein, onthe alkyl groups, in each case, one to seven hydrogen atoms may bereplaced by fluorine;

[0045] and their physiologically acceptable salts;

[0046] provided that when R1, R2, R3 and R4 are all hydrogen, and X—Y—R5is S-phenyl, then R9 is other than phenyl.

[0047] Particular preference is given to compounds of the formula I inwhich

[0048] R1, R2, R3, R4 independently of one another are H, F, Cl, Br, CN;N₃, NO₂, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CH₂-phenyl,O-phenyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl, NH₂,NH—(C₁-C₈)-alkyl, N[(C₁-C₈)-alkyl]₂, COOH, CO—O(C₁-C₈)-alkyl,(C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,wherein on the alkyl, alkenyl and alkynyl groups, in each case, one toseven hydrogen atoms may be replaced by fluorine,

[0049] or an aryl radical wherein the aryl radical is phenyl,

[0050] or heterocycle wherein heterocycle is 1-imidazolyl;

[0051] where the aryl radical or heterocycle may be substituted up totwo times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃, or O—(C₁-C₄)-alkyl,and wherein, on the alkyl groups, one to seven hydrogen atoms may bereplaced by fluorine;

[0052] X S, SO₂;

[0053] Y is (CH₂)_(p), where p may be 0 or 1;

[0054] R5 is CF₃, or (C₁-C₈)-alkyl, wherein, on,the alkyl groups, one toseven hydrogen atoms may be replaced by fluorine; or R5 is

[0055] phenyl, pyridinyl, where the rings of the phenyl and pyridinylmay be substituted up to two times by F, Cl, Br, or (C₁-C₈)-alkyl;

[0056] R9 is F, Cl, Br, (C₁-C₈)-alkyl, wherein, on, the alkyl groups,one to seven hydrogen atoms may be replaced by fluorine; or R9 is

[0057] (CH₂)_(u)-phenyl, where phenyl may be substituted up to two timesby F, Cl, Br, (C₁-C₈)-alkyl;

[0058] and their physiologically acceptable salts;

[0059] provided that when R1, R2, R3 and R4 are all hydrogen, and X—Y—R5is S-phenyl, then R9 is other than phenyl.

[0060] The invention relates to compounds of the formula I in the formof their racemates, racemic mixtures and pure enantiomers, and also totheir diastereomers and mixtures thereof.

[0061] The alkyl, alkenyl and alkynyl radicals in the substituents R1,R2, R3, R4, R5, R6, R7, R8 and R9 can be straight-chain or branched.

[0062] Heterocycle or heterocyclic radical is to be understood asmeaning ring systems which, in addition to carbon, also containheteroatoms, such as, for example, nitrogen, oxygen or sulfur. Thisdefinition furthermore includes ring systems in which the heterocycle orheterocyclic radical is fused with benzene rings. Preferred heterocyclesor heterocyclic radicals are:

[0063] heteroaryls, such as

[0064] benzimidazolyl,

[0065] 1-[(C₁-C₆)-alkyllbenzimidazolyl,

[0066] imidazolyl,

[0067] 2- or 3-thienyl,

[0068] 2- or 3-furyl,

[0069] benzoxazolyl,

[0070] benzothiazolyl,

[0071] 2-, 3- or 4-pyridyl,

[0072] pyrimidinyl,

[0073] 4-, 5- or 6-pyridazin-2H-yl-3-one,

[0074] 4-, 5- or 6-pyridazin-2-(C₁-C₈)-alkyl-2H-yl-3-one,

[0075] 2-benzyl-4-, -5- or -6-pyridazin-2H-yl-3-one,

[0076] 3- or 4-pyridazinyl,

[0077] 2-, 3-, 4- or 8-quinolinyl,

[0078] 1-, 3- or 4-isoquinolinyl,

[0079] 1-phthalazinyl,

[0080] 3- or 4-cinnolinyl,

[0081] 2- or 4-quinazolinyl,

[0082] 2-pyrazinyl,

[0083] 2-quinoxalinyl,

[0084] 2-, 4- or 5-oxazolyl,

[0085] 3-, 4- or 5-isoxazolyl,

[0086] 2-, 4- or 5-thiazolyl,

[0087] 3-, 4- or 5-isothiazolyl,

[0088] 1-[(C₁-C₆)-alkyl]-2-, -4- or -5-imidazolyl,

[0089] 3-, 4- or 5-pyrazolyl,

[0090] 1-[(C₁-C₆)-alkyl]-3-, -4- or -5-pyrazolyl,

[0091] 1- or 4-[1,2,4]-triazolyl,

[0092] 4- or 5-[1,2,3]-triazolyl,

[0093] 1-[(C₁-C₆)-alkyl]-4- or -5-[1,2,3]triazolyl,

[0094] 3-, 4- or 7-indolyl,

[0095] N-[(C₁-C₆)-alkyl]-3-, -4- or -7-indolyl

[0096] 2-[(C₁-C₆)-alkyl]-3(2H )-indazolyl,

[0097] 1-[(C₁-C₆)-alkyl]-3(1H)-indazolyl,

[0098] 5-tetrazolyl,

[0099] 1-[(C₁-C₆)-alkyl]-1H-tetrazolyl,

[0100] 2-[(C₁-C₆)-alkyl]-2H-tetrazolyl.

[0101] Physiologically acceptable salts, which may also be termedpharmaceutically acceptable salts, are particularly suitable for medicalapplications, due to their greater solubility in water compared with thestarting or base compounds. Said salts must have a pharmaceuticallyacceptable anion or cation. Suitable pharmaceutically acceptable acidaddition salts of the basic compounds of the invention are salts ofinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, metaphosphoric acid, nitric acid and sulfuric acid and also oforganic acids such as, for example, acetic acid, benzenesulfonic acid,benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconicacid, glycolic acid, isethionic acid, lactic acid, lactobionic acid,maleic acid, malic acid, methane-sulfonic acid, succinic acid,p-toluenesulfonic acid, tartaric acid and trifluoroacetic acid. Formedicinal purposes, particular preference is given to using the chlorinesalt. Suitable pharmaceutically acceptable basic salts of the acidiccompounds of the invention are ammonium salts, alkali metal salts (suchas sodium salts and potassium salts) and alkaline earth metal salts(such as magnesium salts and calcium salts).

[0102] Salts having a pharmaceutically unacceptable anion are likewiseincluded within the scope of the present invention as usefulintermediates for preparing or purifying compound of the inventionand/or for use in nontherapeutic applications, for example in-vitroapplications.

[0103] The term “physiologically functional derivative” used hereinrelates to any physiologically acceptable derivative of an inventivecompound of the formula I, for example an ester which on administrationto a mammal, for example humans, is capable of forming (directly orindirectly) a compound of the formula I or an active metabolite thereof.

[0104] The physiologically functional derivatives also include prodrugsof the compounds of the invention. Such prodrugs may be metabolized invivo to a compound of the invention. These prodrugs may or may not beactive themselves.

[0105] The physiologically functional derivatives furthermore include,for example, glucuronides, sulfuric acid esters, glycosides andribosides.

[0106] The compounds of the invention may also be present in variouspolymorphous forms, for example as amorphous and crystallinepolymorphous forms. All polymorphous forms of the compounds of theinvention are included within the scope of the invention and are anotheraspect of the invention.

[0107] All references to “compound(s) according to formula (I)” referhereinbelow to a compound/compounds of the formula (I) as describedabove and also to their salts, solvates and physiologically functionalderivatives as described herein.

[0108] The amount of a compound according to formula (I) which isrequired in order to attain the desired biological effect, i.e., thepharmaceutically effective amount, depends on a number of factors, forexample the specific compound selected, the intended use, the type ofadministration and the clinical state of the patient. In general, thedaily dose is in the range from 0.3 mg to 100 mg (typically from 3 mg to50 mg) per day per kilogram of body weight, for example 3-10 mg/kg/day.An intravenous dose can be, for example, in the range from 0.3 mg to 1.0mg/kg and can be administered in a suitable manner as an infusion of 10ng to 100 ng per kilogram per minute. Suitable infusion solutions forthese purposes may contain, for example, from 0.1 ng to 10 mg, typicallyfrom 1 ng to 10 mg per milliliter. Individual doses may contain, forexample, from 1 mg to 10 g of the active compound. Thus, ampules forinjections can contain, for example, from 1 mg to 100 mg, and orallyadministerable individual dose formulations such as, for example,tablets or capsules can contain, for example, from 1.0 to 1000 mg,typically from 10 to 600 mg. In the case of pharmaceutically acceptablesalts, the abovementioned masses relate to the mass of the compounds ofthe formula I on which the salt is based. The compound used for theprophylaxis or therapy of the abovementioned conditions may be thecompounds according to formula (I) themselves, but they are preferablypresent in the form of a pharmaceutical composition together with anacceptable carrier. The carrier must be naturally acceptable, in thesense that it is compatible with the other ingredients of saidcomposition and is not harmful to the patient's health. The carrier maybe a solid or a liquid or both and is preferably formulated with thecompound as an individual dose, for example as a tablet which maycontain from 0.05% to 95% by weight of the active compound. Furtherpharmaceutically active substances may also be present, includingfurther compounds according to formula (I). The pharmaceuticalcompositions of the invention may be prepared according to any of theknown pharmaceutical methods which essentially comprise mixing theingredients with pharmacologically acceptable carriers, which may alsobe termed pharmaceutically acceptable carriers and/or excipients.

[0109] Pharmaceutical compositions of the invention are those which aresuitable for oral, rectal, topical, peroral (e.g. sublingual) andparenteral (e.g. subcutaneous, intramuscular, intradermal orintravenous) administration, although the most suitable manner ofadministration depends in each individual case on the nature andseverity of the condition to be treated and on the nature of thecompound according to formula (I) used in each case. Sugar-coatedformulations and sugar-coated delayed-release formulations, too, areincluded within the scope of the invention. Preference is given toacid-resistant and enteric formulations. Suitable enteric coatingsinclude cellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose phthalate and anionic polymers ofmethacrylic acid and methyl methacrylate.

[0110] Suitable pharmaceutical compositions for oral administration maybe present in separate units as, for example, capsules, cachets,lozenges or tablets, which in each case contain a particular amount ofthe compound according to formula (I); as powders or granules; assolution or suspension in an aqueous or nonaqueous liquid; or as anoil-in-water or water-in-oil emulsion. As already mentioned, saidcompositions can be prepared according to any suitable pharmaceuticalmethod which includes a step in which the active compound and thecarrier (which may comprise one or more additional components) arecontacted. In general, the compositions are prepared by uniform andhomogeneous mixing of the active compound with a liquid and/or finelydispersed solid carrier, after which the product is shaped, ifnecessary. Thus a tablet, for example, may be prepared by pressing orshaping a powder or granules of the compound, where appropriate with oneor more additional components. Pressed tablets can be prepared bytableting the compound in free-flowing form, for example a powder orgranules, mixed, where appropriate, with a binder, lubricant, inertdiluent and/or one or more surface active/dispersing agents in asuitable machine. Shaped tablets can be prepared by shaping thepulverulent compound, moistened with an inert liquid diluent, in asuitable machine.

[0111] Pharmaceutical compositions which are suitable for peroral(sublingual) administration include lozenges which contain a compoundaccording to formula (I) with a flavoring, usually sucrose and gumarabic or tragacanth, and pastilles which comprise the compound in aninert base such as gelatin and glycerol or sucrose and gum arabic.

[0112] Suitable pharmaceutical compositions for parenteraladministration preferably comprise sterile aqueous preparations of acompound according to formula (I) which are preferably isotonic with theblood of the intended recipient. These preparations are preferablyadministered intravenously, although they may also be administeredsubcutaneously, intramuscularly or intradermally as an injection. Saidpreparations may preferably be prepared by mixing the compound withwater and rendering the obtained solution sterile and isotonic with theblood. Injectable compositions of the invention generally contain from0.1 to 5% by weight of the active compound.

[0113] Suitable pharmaceutical compositions for rectal administrationare preferably present as individual dose suppositories. These may beprepared by mixing a compound according to formula (I) with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

[0114] Suitable pharmaceutical compositions for topical application tothe skin are preferably present as ointment, cream, lotion, paste,spray, aerosol or oil. Carriers which may be used are petroleum jelly,lanolin, polyethylene glycols, alcohols and combinations of two or moreof these substances. In general, the active compound is present at aconcentration of from 0.1 to 15%, for example from 0.5 to 2%, by weightof the composition.

[0115] Transdermal administration is also possible. Suitablepharmaceutical compositions for transdermal administration may bepresent as individual patches which are suitable for long-term closecontact with the epidermis of the patient. Such patches suitably containthe active compound in an optionally buffered aqueous solution,dissolved and/or dispersed in an adhesive or dispersed in a polymer. Asuitable active compound concentration is from approx. 1% to 35%,preferably approx. 3% to 15%. A particular possibility is the release ofthe active compound by electro-transport or iontophoresis, as described,for example, in Pharmaceutical Research, 2(6): 318 (1986).

[0116] The invention furthermore provides a process for preparing thecompounds of the formula I which comprises obtaining the compounds ofthe formula I by proceeding according to the reaction scheme below:

[0117] To this end, compounds of the formula II,

[0118] in which R1, R2, R3 and R4 are as defined above are convertedwith a halogen, such as, for example, bromine or chlorine, into acompound of the formula III. The compounds of the formula III areconverted further with metal salts of thiols of the formula H—X—Y—R5,where X is sulfur and Y and R5 are as defined above into compounds ofthe formula I where X═S and R9=H. These metal salts can be employed assuch or they can be generated in solution in situ from the thiol and abase, such as, for example, aqueous sodium hydroxide.

[0119] On the other hand, compounds of the formula I where X═S and R9=Hcan be obtained by reacting compounds of the formula II with a base,such as, for example, lithium diisopropylamide, for example intetrahydrofuran, and with a disulfide of the formula R5-Y—X—X—Y—R5 inwhich R5 and Y are as defined above and X═S; alternatively, instead ofthe disulfide, it is also possible to use a sulfenyl chloride of theformula Cl—X—Y—R5 where X═S and Y and R5 are as defined above (see, forexample, D. Seebach et al.; Chem. Ber. 109, 1601-1616 (1976)).

[0120] Compounds of the formula I in which X═S and R9 is not hydrogencan be obtained, for example, as follows: compounds of the formula IIare subjected, for example, to a fluorination, alkylation or acondensation with an aldehyde and subsequent reduction, giving compoundsof the formula IV which for their part can be converted, for exampleafter bromination with compounds of the formula M⁺⁻X—Y—R5, where X═S andY and R5 are as defined above, to compounds of the formula I where X═Sand R9 is not hydrogen.

[0121] Compounds of the formula I in which X═SO and R9 is not hydrogencan be prepared for example, by selective oxidation of the compound ofthe formula I in which X═S, using one equivalent ofperoxytrifluoroacetic acid (C. G. Venier et al.; J. Org. Chem. 47, 3773(1982)). The preparation of the sulfoxides from the sulfides can also becarried out using manganese dioxide or chromic acid (D. Edwards et al.;J. Chem. Soc. 1954, 3272). Furthermore suitable for this oxidation ishydrogen peroxide in acetic anhydride (A. V. Sviridova et al.; J. Org.Chem (Russ), English Transl.; 7, 2577 (1971)).

[0122] Compounds of the formula I in which X═SO₂ and R9 is not hydrogencan be obtained by oxidation using, for example, 2KHSO₅×KHSO₄×K₂SO₄(Oxone), either from compounds of the formula I in which X═S and R9 isnot hydrogen or from compounds of the formula I in which X═SO and R9 isnot hydrogen (see, for example, M. Hudlický, Oxidations in OrganicChemistry, ACS Monograph 186, American Chemical Society, Washington,D.C., 1990).

[0123] Compounds of the formula I in which X═S, SO or SO₂ and R9 is nothydrogen, for example where R9 is phenyl, and Y is a bond and R5 is asdescribed above can also be obtained by reacting compounds of theformula I in which X═S-phenyl and R9=H and Y is a bond and R5 is asdescribed above with, for example, diphenyliodonium chloride. Theresulting compounds can either be converted stepwise into thecorresponding compounds in which X═SO or SO₂, or they are subsequentlydesulfurized with zinc/acetic acid and are then available for furtherreactions according to the scheme above.

[0124] Compounds of the formula I in which X═SO or SO₂, R9=H and Y=abond (═(CH₂)m where m=0) can also, alternatively, be prepared accordingto the scheme below (shown for the preparation of the aryl sulfoxides(H. J. Monteiro et al.; Tetrahedron Letters 11, 921-924 (1975) and arylsulfones (A. K. Maiti et al.; Tetrahedron 50, 10483-10490 (1994)):

[0125] Compounds of the formula I in which X═SO₂ and R9 is not hydrogenand Y and R5 are as defined above can also be obtained by subjectingcompounds of the formula I in which X═SO₂ and R9=H and Y and R5 are asdefined above to a fluorination or alkylation, for example.

[0126] Inorganic acids suitable for forming salts are, for example:hydrohalic acids, such as hydrochloric acid and hydrobromic acid, andalso sulfuric acid, phosphoric acid and amidosulfonic acid.

[0127] Organic acids suitable for salt formation which may be mentionedare, for example: formic acid, acetic acid, benzoic acid,p-toluenesulfonic acid, benzenesulfonic acid, succinic acid, fumaricacid, maleic acid, lactic acid, tartaric acid, citric acid, L-ascorbicacid, salicylic acid, isethionic acid, methanesulfonic acid,trifluoromethanesulfonic acid, 1,2-benzisothiazol-3(2H)-one,6-methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide.

[0128] The examples shown below serve to illustrate the inventionwithout limiting it. The melting points or decomposition points (m.p.)measured are uncorrected and generally depend on the heating rate.

[0129] The retention times given in the table below refer to thefollowing methods for determination:

[0130] Method A: Column: Merck, LiChroCart 55-2, PuroSpher STAR, RP 18e; measured at 254 nm; gradient: solvent A acetonitrile/water 90:10+0.5%formic acid; solvent B acetonitrile/water 10:90+0.5% formic acid; flowrate: 0.750 ml/min; time (min)/solvent B (%): 0.00/95.0, 0.50/95.0,1.75/5.0, 4.25/5.0, 4.50/95.0, 5.00/95.0; temperature: 40° C.:

[0131] Method B: column: YMC J'sphere, 33×2, ODS H 80 4 μ; measured at254 nm; gradient: solvent A acetonitrile+0.5% formic acid; solvent Bwater+0.5% formic acid; flow rate: 1.00 ml/min; time (min)/solvent B(%): 0.00/90.0, 2.50/5.0, 3.30/5.0, 3.35/90.0; temperature: 30° C.:

EXAMPLES

[0132] Table 1:

Formula I Example R1 R2 R3 R4 X Y R5 R9 m.p.[° C.] 1 H Cl H H SO₂ — CH₃F 150 [MH⁺] 2 H Cl H H SO₂ — CH₃ CH₂Ph 335.2 3 H OCH₃ OCH₃ H SO₂ — CH₃ F289.2 Retention time in min (method A or B 4 H Cl H H S — Pyridin-2-yl F 2.789 (A) 5 H Cl H H S CH₂ CF₃ F  2.699 (B) 6 H H H H S — C₆H₄-4-Cl F 3.096 (A) 7 H Cl H H SO₂ — Pyridin-2-yl F  1.460 (B) 8 H Cl H H SO₂ CH₂CF₃ F  1.514 (B) 9 H C₆H₄- H H SO₂ — CH₃ F  2.628 4-Cl (B) 10 H CF₃ H HSO₂ — CH₃ F  2.261 (B) 11 H H C₆H₄-4- H SO₂ — CH₃ F  2.656 CF₃ (B) 12 BrH H H SO₂ — CH₃ F  2.182 (B) 13 H N- H H SO₂ — CH₃ F  2.221 (B) phthali-midoyl

[0133] The compounds of the formula I are distinguished by beneficialactions on the metabolism of lipids, and they are particularly suitablefor weight reduction and, after weight reduction, for maintaining areduced weight in mammals and as anorectic agents. The compounds aredistinguished by their low toxicity and their few side effects. Thecompounds may be employed alone or in combination with otherweight-reducing or anorectic active compounds. Further anorectic activecompounds of this kind are mentioned, for example, in the Rote Liste,Chapter 01 under weight-reducing agents/appetite suppressants, and mayalso include those active compounds which increase the energy turnoverof the organism and thus lead to weight reduction or else those whichinfluence the general metabolism of said organism such that increasedcalorie intake does not cause an enlargement of the fat depots and anormal calorie intake causes a reduction in the fat depots of saidorganism. The compounds are suitable for the prophylaxis and, inparticular, for the treatment of problems of excess weight or obesity.The compounds are furthermore suitable for the prophylaxis and, inparticular, for the treatment of type II diabetes, of arteriosclerosisand for the normalization of lipid metabolism and for the treatment ofhigh blood pressure.

[0134] In a further aspect of the invention, the compounds of theformula I may be administered in combination with one or more furtherpharmacologically active substances which may be selected, for example,from the group consisting of antidiabetics, antiadipose agents,blood-pressure-lowering active compounds, lipid reducers and activecompounds for the treatment and/or prevention of complications caused bydiabetes or associated with diabetes.

[0135] Suitable antidiabetics include insulins, amylin, GLP-1 and GLP-2derivatives such as, for example, those disclosed by Novo Nordisk A/S inWO 98/08871 and also oral hypoglycemic active compounds.

[0136] Said oral hypoglycemic active compounds preferably includesulfonyl ureas, biguanides, meglitinides, oxadiazolidinediones,thiazolidinediones, glucosidase inhibitors, glucagon receptorantagonists, GLP-1 agonists, potassium channel openers such as, forexample, those disclosed by Novo Nordisk A/S in WO 97/26265 and WO99/03861, insulin sensitizers, activators of insulin receptor kinase,inhibitors of liver enzymes involved in the stimulation ofgluconeogenesis and/or glycogenolysis, for example glycogenphosphorylase inhibitors, modulators of glucose uptake and glucoseelimination, lipid metabolism-modifying compounds such asantihyperlipidemic active compounds and antilipidemic active compounds,for example HMGCoA-reductase inhibitors, inhibitors of cholesteroltransport/cholesterol uptake, inhibitors of the reabsorption of bileacid or inhibitors of microsomal triglyceride transfer protein (MTP),compounds which reduce food intake, PPAR and RXR agonists and activecompounds which act on the ATP-dependent potassium channel of betacells.

[0137] In one embodiment of the present invention, the present compoundsare administered in combination with insulin.

[0138] In another embodiment, the compounds of the invention areadministered in combination with a sulfonylurea such as, for example,tolbutamide, glibenclamide, glimepiride, glipizide, gliquidone,glisoxepide, glibornuride or gliclazide.

[0139] In another embodiment, the compounds of the present invention areadministered in combination with a biguanide such as, for example,metformin.

[0140] In another embodiment, the compounds of the present invention areadministered in combination with a meglitinide such as, for example,repaglinide.

[0141] In yet another embodiment, the compounds of the present inventionare administered in combination with a thiazolidinedione such as, forexample, troglitazone, ciglitazone, pioglitazone, rosiglitazone or thecompounds disclosed by Dr. Reddy's Research Foundation in WO 97/41097,in particular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

[0142] In yet another embodiment, the compounds of the present inventionare administered in combination with a monoamine oxidase inhibitor suchas disclosed, for example, in WO 01/12176. Particularly suitable forthis purpose are[3(S),3a(S)]-3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one,(R)-5-(methoxymethyl)-3-[6-(4,4,4-trifluorobutoxy)benzofuran-3-yl]oxazolidin-2-oneor(R)-5-(methoxymethyl)-3-[6-cyclopropylmethoxybenzofuran-3-yl]oxazolidin-2-one.

[0143] In another embodiment, the compounds of the present invention areadministered in combination with an α-glucosidase inhibitor such as, forexample, miglitol or acarbose.

[0144] In yet another embodiment, the present compounds are administeredin combination with an hCNTF (human ciliary neurotrophic factor) orderivatives thereof, such as, for example, CNTF_(AX15) or modifiedCNTF_(AX15), such as disclosed, for example, in Lambert et al., PNAS 98,4652-4657.

[0145] In another embodiment, the compounds of the present invention areadministered in combination with an active compound which acts on theATP-dependent potassium channel of the beta cells, such as, for example,tolbutamide, glibenciamide, glimepiride, glipizide, gliclazide orrepaglinide.

[0146] In yet another embodiment, the compounds of the present inventionare administered in combination with an antihyperlipidemic activecompound or an antilipidemic active compound such as, for example,cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin,pravastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin,probucol, ezetimibe or dextrothyroxine.

[0147] In another embodiment, the compounds of the present invention areadministered in combination with more than one of the aforementionedcompounds, for example in combination with a sulfonylurea and metformin,a sulfonylurea and acarbose, repaglinide and mefformin, insulin and asulfonylurea, insulin and metformin, insulin and troglitazone, insulinand lovastatin, etc.

[0148] Furthermore, the compounds of the invention may be administeredin combination with one or more antiadipose agents orappetite-controlling active compounds.

[0149] Such active compounds may be selected from the group consistingof CART agonists, NPY antagonists, melanocortin 3 or 4 (MC3 or MC4)agonists, melanin-concentrating hormone (MCH) antagonists, orexinantagonists, H3 agonists, TNF agonists, CRF agonists, CRF BPantagonists, urocortin agonists, β3 adrenoceptor agonists, CCK agonists,serotonin re-uptake inhibitors, mixed serotonin and noradrenalinreuptake inhibitors, 5HT modulators, bombesin agonists, galaninantagonists, glucocorticoid receptor modulators, growth hormone,growth-hormone-releasing compounds, TRH agonists, uncoupling protein 2or 3 modulators, leptin receptor agonists, leptin mimetics, dopamineagonists (bromocriptine, doprexin), lipase/amylase inhibitors,cannabinoid receptor 1 antagonists, modulators of acylation-stimulatingprotein (ASP), PPAR modulators, RXR modulators or TR-β agonists.

[0150] In one embodiment of the invention, the antiadipose agent isleptin or modified leptin.

[0151] In another embodiment, the antiadipose agent is dexamphetamine oramphetamine.

[0152] In another embodiment, the antiadipose agent is fenfluramine ordexfenfluramine.

[0153] In yet another embodiment, the antiadipose agent is sibutramineor the mono- and bis-demethylated active metabolite of sibutramine.

[0154] In another embodiment, the antiadipose agent is orlistate.

[0155] In another embodiment, the antiadipose agent is mazindol,diethylpropione or phentermine.

[0156] Furthermore, the compounds of the present invention may beadministered in combination with one or more antihypertensive activecompounds. Examples of antihypertensive active compounds arebetablockers such as alprenolol, atenol, timolol, pindolol, propanololand metoprolol, ACE (angiotensin-converting enzyme) inhibitors such as,for example, benazepril, captopril, enalapril, fosinopril, lisinopril,quinapril and rampril, calcium channel blockers such as nifedipine,felodipine, nicardipine, isradipine, nimodipine, diltiazem andverapamil, and also alphablockers such as doxazosin, urapidil, prazosinand terazosin. Furthermore, reference may be made to Remington: TheScience and Practice of Pharmacy, 19th edition, Gennaro, editor, MackPublishing Co., Easton, Pa., 1995.

[0157] The present invention provides for methods for reducing weight inmammals in need thereof, methods for the prophylaxis or treatment ofobesity in mammals in need thereof, and methods for the prophylaxis ortreatment of type II diabetes in mammals in need thereof, comprisingadministering to such mammals pharmaceutically effective amounts ofcompounds of the present invention.

[0158] The present invention provides also for methods for reducingweight in mammals in need thereof, methods for the prophylaxis ortreatment of obesity in mammals in need thereof, and methods for theprophylaxis or treatment of type II diabetes in mammals in need thereof,comprising administering to such mammals pharmaceutically effectiveamounts of compounds of the present invention, in combination withpharmaceutically effective amounts of further pharmacologically activecompounds suitable for reducing weight in mammals.

[0159] It is self-evident that every suitable combination of thecompounds of the invention with one or more of the aforementionedcompounds and optionally one or more other pharmacologically activesubstances is to be regarded as covered by the scope of protection ofthe present invention.

[0160] The activity of the compounds was assayed as follows:

[0161] Biological Test Model:

[0162] The anorectic action was tested on female NMRI mice. Afterremoval of feed for 24 hours, the preparation to be tested wasadministered intraperitoneally (ip) or by gavage (po). The animals werehoused singly and, with free access to drinking water, they were offeredevaporated milk 30 minutes after administration of the preparation. Theconsumption of evaporated milk was determined and the general behaviorof the animals was monitored every half an hour for 7 hours. Themeasured milk consumption was compared to that of vehicle-treatedcontrol animals. TABLE 2 Anorectic action, measured as a reduction inthe cumulative milk consumption by treated animals compared with controlanimals Compound/ Example

Formula I Dose [mg/kg] Number of animals/ cumulative milk consumption bytreated animals N/[ml] Number of animals/ cumulative milk consumption byuntreated control animals N/[ml] Reduction in cumulative milkconsumption as % of the control Example 1 20 5/2.00 5/3.86 48

[0163] The table indicates that the compounds of the formula I exhibitvery good anorectic action.

[0164] The preparation of some-examples is described in detail below;the other compounds of the formula I were obtained analogously:

Example 1

[0165] 5-Chloro-2- fluoro-2-methanesulfonylindan-1-one:

[0166] 1. 5-Chloro-2-methylsulfanylindan-1-one:

[0167] 0.98 g (4 mmol) of 2-bromo-5-chloroindan-1-one and 0.42 g (6mmol) of sodium thiomethoxide are suspended in 5 ml of ethanol, treatedin an ultrasonic bath for 30 minutes and then stirred at roomtemperature for 90 minutes. The reaction mixture is concentrated underreduced pressure and chromatographed on silica gel using toluene/ethylacetate 10/1. The eluates are concentrated under reduced pressure,giving 5-chloro-2-methylsulfanylindan-1-one of melting point 90° C.

[0168] 2. 5-Chloro-2-methanesulfonylindan-1-one:

[0169] 0.5 g (2.35 mmol) of 5-chloro-2-methylsulfanylindan-1-one isdissolved in 10 ml of methanol; at 0° C., a solution of 4.33 g (7.05mmol) of 2KHSO₅×KHSO₄×K₂SO₄ in 10 ml of water is added dropwise. Themixture is stirred at room temperature for 5 h; the methanol isdistilled off and the aqueous residue is extracted with dichloromethane.The organic phase is separated off, dried over MgSO₄, filtered andconcentrated under reduced pressure. This gives 0.5 g of5-chloro-2-methanesulfonylindan-1-one of melting point 197° C.

[0170] 3. 5-Chloro-2-fluoro-2-methanesulfonylindan-1-one:

[0171] 0.734 g (3 mmol) of 5-chloro-2-methanesulfonylindan-1-one and1.77 g (5 mmol) of N-fluoro-N′-(chloromethyl)triethylenediaminebis(tetrafluoroborate) are suspended in a mixture of 2.5 ml of water and7.5 ml of acetonitrile and stirred under reflux for 4 h. The reactionmixture is cooled, concentrated under reduced pressure and purifiedchromatographically on silica gel using the mobile phasedichloromethane. This gives5-chloro-2-fluoro-2-methanesulfonylindan-1-one of melting point 150° C.

Example 2

[0172] 2-Benzyl-5-chloro-2-methanesulfonylindan-1-one:

[0173] 1. Methyl 2-benzyl-5-chloro-1-oxoindane-2-carboxylate:

[0174] 1.11 ml of diisopropylamine are dissolved in 25 ml of drytetrahydrofuran, 6.9 ml of N-butyllithium in n-hexane (15%) are added at−50° C., and the mixture is stirred at −10° C. for 20 minutes. At −50°C., 2.25 g of methyl 5-chloro-1-oxoindane-2-carboxylate, dissolved in 25ml of tetrahydrofuran, are then added dropwise. The mixture is stirredat −50° C. for 30 min, and a solution of 1.31 ml of benzyl bromide in 5ml of tetrahydrofuran is then added dropwise. The reaction mixture isstirred at room temperature for 20 h. To bring the reaction tocompletion, another 1.31 ml of benzyl bromide are added and the mixtureis heated under reflux for 72 h. 20 ml of saturated sodium bicarbonatesolution are added to the reaction mixture, which is then diluted withethyl acetate. The organic phase is separated off, washed with saturatedsodium chloride solution, dried over magnesium sulfate, filtered andconcentrated under reduced pressure. This gives methyl2-benzyl-5-chloro-1-oxoindane-2-carboxylate having a molecular weight of314 (C₁₈H₁₅ClO₃); MS (ESI): 315.1 (MH⁺).

[0175] 2. 2-Benzyl-5-chloroindan-1-one:

[0176] The compound of example 2.1 is suspended in a mixture of 10 ml ofethanol and 10 ml of 5% strength aqueous sodium hydroxide solution andstirred at 40° C. for one hour. The alcohol is then removed underreduced pressure and the residue is extracted with ethyl acetate. Theorganic phase is washed with water until neutral, dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The residueis purified chromatographically on silica gel using n-heptane/ethylacetate 2/1. This gives 2-benzyl-5-chloroindan-1-one having a molecularweight of 256 (C₁₆H₁₃ClO); MS (ESI): 256.8 (MH⁺).

[0177] 3. 2-Benzyl-2-bromo-5-chloroindan-1-one:

[0178] 0.86 g of the compound of example 2.2 is dissolved in 4 ml ofacetic acid, 50 μl of 48% strength HBr solution and 0.207 ml of bromineare added and the mixture is stirred at room temperature for one hour.The crude product is purified chromatographically on silica gel usingtoluene. This gives 2-benzyl-2-bromo-5-chloroindan-1-one having amolecular weight of 334 (C₁₆H₁₂BrClO); MS (ESI): 334.8 (MH⁺).

[0179] 4. 2-Benzyl-5-chloro-2-methanesulfonylindan-1-one:

[0180] 1 mmol of the compound of example 2.3 and 1.2 mmol ofmethanesulfinic acid sodium salt in 3 ml of dimethylformamide arestirred at 70° C. for 4 hours. The crude product is purifiedchromatographically on silica gel using n-heptane/ethyl acetate 1/1.This gives 2-benzyl-5-chloro-2-methanesulfonylindan-1-one of molecularweight 334 (C₁₇H₁₅ClO₃S); MS (ESI): 335.2 (MH⁺).

[0181] The compounds of examples 4-6 are obtained by reacting thecorresponding 2-fluroindan-1-one with the sodium salt of thecorresponding mercaptan.

[0182] The compounds of examples 7-13 are obtained as described inexample 1.3 by fluorination of the corresponding sulfonyl derivatives.

What is claimed is:
 1. A compound of the formula I

wherein: R1, R2, R3, R4 independently of one another are H, F, Cl, Br,I, CN; N₃, NO₂, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CH₂-phenyl,O-phenyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl,S(O)₀₋₂(C₁-C₈)-alkyl, S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl,NH—(C₃-C₈)-cycloalkyl, N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂,NH—CO—(C₁-C₈)-alkyl, NH—CO—(C₃-C₈)-cycloalkyl; SO₃H, SO₂—NH₂,SO2-NH—(C₁-C₈)-alkyl, SO₂—NH—(C₃-C₈)-cycloalkyl, NH—SO₂—NH₂,NH—SO₂—(C₁-C₈)-alkyl, NH—SO₂-(C₃-C₈)-cycloalkyl, O—CH₂—COOH,O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O(C₁-C₈)-alkyl,CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂, (C₁-C₈)-alkyl, (C₃-C₈)cycloalkyl, (C₂-C₈)-alkenyl,(C₂-C₈)-alkynyl, wherein on the alkyl, alkenyl and alkynyl groups, ineach case, one to seven hydrogen atoms may be replaced by fluorine, orone hydrogen may be replaced by OH, OC(O)CH₃, O—CH₂-Ph, NH₂, NH—CO—CH₃or N(COOCH₂Ph)₂; an aryl radical wherein the aryl radical is phenyl, or1- or 2-naphthyl; or a heterocycle wherein the heterocycle is5-tetrazolyl, 1-[(C₁-C₆)-alkyl]-5-tetrazolyl,2-[(C₁-C₆)-alkyl]-5-tetrazolyl, 1-imidazolyl, 1- or 4-[1,2,4]-triazolyl,2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or 4-pyridyl, 2-, 4- or5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, or 3-, 4- or5-isothiazolyl, where the aryl radical or heterocycle may be substitutedup to two times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃,O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl, NH₂, NH—SO₂—(C₁-C₄)-alkyl, COOH,CO—O—(C₁-C₄)-alkyl, or CO—NH₂, and wherein on the alkyl groups, one toseven hydrogen atoms may be replaced by fluorine; X is S, SO, or SO₂; Yis (CH₂)_(p), where p may be 0, 1, 2 or 3; R5 is CF₃, (C₁-C₁₈)-alkyl,(C₃-C₄)-cycloalkyl, or (C₆-C₈)-cycloalkyl, wherein, on the alkyl groups,one to seven hydrogen atoms may be replaced by fluorine; or R5 is(CH₂)_(r)—COR6, where r=1-6 and R6 may be OH, O—(C₁-C₆)-alkyl or NH₂; orR5 is CH₂—CH(NHR7)-COR8, where R7 may be H or C(O)—(C₁-C₄)-alkyl and R8may be OH, O—(C₁-C₆)-alkyl or NH₂; or R5 is Phenyl, 1- or 2-naphthyl,biphenyl or a heterocyclic radical, where the rings or ring systems ofthe phenyl, 1- or 2-naphthyl or heterocyclic radical may be substitutedup to two times by F, Cl, Br, I, CN, OH, O(C₁-C₈)-alkyl,O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl,S(O)₀₋₂(C₁-C₈)-alkyl, S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl,NH—(C₃-C₈)-cycloalkyl, N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂,NH—CO—(C₂-C₈)-alkyl, NH—CO—(C₃-C₈)-cycloalkyl; SO₃H, SO₂—NH₂,SO₂—NH—(C₁-C₈)-alkyl, SO₂—NH—(C₃-C₈)-cycloalkyl; NH—SO₂-NH₂,NH—SO₂—(C₁-C₈)-alkyl, NH—SO₂—(C₃-C₈)-cycloalkyl, O—CH₂—COOH,O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O(C₁-C₈)-alkyl,CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂, (C₁-C₈)-alkyl, or (C₃-C₈)-cycloalkyl, wherein onthe alkyl groups, in each case, one to seven hydrogen atoms may bereplaced by fluorine; R9 is F, Cl, Br, CN, CF₃, (C₁-C₁₈)-alkyl,(C₃-C₄)-cycloalkyl, or (C₆-C₈)-cycloalkyl, wherein, on the alkyl groups,one to seven hydrogen atoms may be replaced by fluorine; or R9 is(CH₂)_(r)—COR6, where r=9-16 and R6 may be OH, O—(C₁-C₆)-alkyl or NH₂;or R9 is CH₂—CH(NHR7)-COR8 where R7 may be H or C(O)—(C₁-C₄)-alkyl andR8 may be OH, O—(C₁-C₆)-alkyl or NH₂; or R9 is (CH₂)_(u)-aryl or(CH₂)_(u)-heteroaryl, where u is 0 to 6 and aryl may be phenyl, 1- or2-napthyl, biphenyl or a heterocyclic radical, where the rings or ringsystems of aryl, heteroaryl or the heterocyclic radical may besubstituted up to two times by F, Cl, Br, I, CN, OH, O(C₁-C₈)-alkyl,O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl,S(O)₀₋₂(C₁-C₈)-alkyl, S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl,NH—(C₃-C₈)-cycloalkyl, N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂,NH—CO—(C₂-C₈)-alkyl, NH—CO—(C₃-C₈)-cycloalkyl; SO₃H, SO₂—NH₂,SO₂—NH—(C₁-C₈)-alkyl, SO₂—NH—(C₃-C₈)-cycloalkyl; NH—SO₂—NH₂,NH—SO₂—(C₁-C₈)-alkyl, NH—SO₂—(C₃-C₈)-cycloalkyl, O—CH₂—COOH,O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O(C₁-C₈)-alkyl,CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂, (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, wherein on thealkyl groups, in each case, one to seven hydrogen atoms may be replacedby fluorine; or a physiologically acceptable salt thereof; provided thatwhen R1, R2, R3 and R4 are all hydrogen, and X—Y—R5 is S-phenyl, then R9is other than phenyl.
 2. A compound according to claim 1 of the formulaI, wherein R1, R2, R3, R4 independently of one another are H, F, Cl, Br,CN; N₃, NO₂, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CH₂-phenyl,O-phenyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl, NH₂,NH—(C₁-C₈)-alkyl, N[(C₁-C₈)-alkyl]₂, COOH, CO—O(C₁-C₈)-alkyl,(C₁-C₈)-alkyl, (C₃-C₈)cycloalkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,wherein, on the alkyl, alkenyl and alkynyl groups, in each case, one toseven hydrogen atoms may be replaced by fluorine; an aryl radicalwherein the aryl radical is phenyl, or a heterocycle wherein theheterocycle is 1-imidazolyl, where the aryl radical or heterocycle maybe substituted up to two times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃,O—(C₁-C₄)-alkyl, and wherein, on the alkyl groups, one to seven hydrogenatoms may be replaced by fluorine; X is S, SO, SO₂; Y is (CH₂)_(p),where p may be 0, 1, 2 or 3; R5 is CF₃, or (C₁-C₁₈)-alkyl, wherein, onthe alkyl groups one to seven hydrogen atoms may be replaced byfluorine; or R5 is (CH₂)_(r)—COR6, where r is 1 to 6 and R6 may be OH,O—(C₁-C₆)-alkyl or NH₂; or R5 is CH₂—CH(NHR7)-COR8, where R7 may be H orC(O)—(C₁-C₄)-alkyl and R8 may be OH, O—(C₁-C₆)-alkyl or, NH₂; or R5 isPhenyl, 1- or 2-naphthyl, biphenyl or a heterocyclic radical, where therings or ring systems may be substituted up to two times by F, Cl, Br,I, CN, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl,O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl,N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₂-C₈)-alkyl,NH—CO—(C₃-C₈)-cycloalkyl; SO₃H, SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,SO₂—NH—(C₃-C₈)-cycloalkyl; NH—SO₂—NH₂, NH—SO₂—(C₁-C₈)-alkyl,NH—SO₂—(C₃-C₈)-cycloalkyl, O—CH₂-COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH,CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂, (C₁-C₈)-alkyl, or (C₃-C₈)-cycloalkyl, wherein, onthe alkyl groups, in each case, one to seven hydrogen atoms may bereplaced by fluorine; R9 is F, Cl, Br, CN, CF₃, (C₁-C₁₈)-alkyl,(C₃-C₄)-cycloalkyl, or (C₆-C₈)-cycloalkyl, wherein, on the alkyl groups,one to seven hydrogen atoms may be replaced by fluorine; or R9 is(CH₂)_(u)-aryl or (CH₂)_(u)-heteroaryl, where u is 0 to 6 and aryl maybe phenyl, 1- or 2-napthyl, biphenyl or a heterocyclic radical, wherethe rings or ring systems of aryl, heteroaryl, or the heterocyclicradical may be substituted up to two times by F, Cl, Br, I, CN, OH,O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl,O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl,N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₂-C₈)-alkyl,NH—CO—(C₃-C₈)-cycloalkyl; SO₃H, SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,SO₂—NH—(C₃-C₈)-cycloalkyl; NH—SO₂—NH₂, NH—SO₂—(C₁-C₈)-alkyl,NH—SO₂—(C₃-C₈)-cycloalkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH,CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl,CO—N[(C₁-C₈)-alkyl]₂, (C₁-C₈)-alkyl, or (C₃-C₈)-cycloalkyl, wherein, onthe alkyl groups, in each case, one to seven hydrogen atoms may bereplaced by fluorine; and their physiologically acceptable salts;provided that when R1, R2, R3 and R4 are all hydrogen, and X—Y—R5 isS-phenyl, then R9 is other than phenyl.
 3. A compound according to claim1 of the formula I wherein R1, R2, R3, R4 independently of one anotherare H, F, Cl, Br, CN; N₃, NO₂, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl,O—CH₂-phenyl, O-phenyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl,NH₂, NH—(C₁-C₈)-alkyl, N[(C₁-C₈)-alkyl]₂, COOH, CO—O(C₁-C₈)-alkyl,(C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,wherein on the alkyl, alkenyl and alkynyl groups, in each case, one toseven hydrogen atoms may be replaced by fluorine, or an aryl radicalwherein the aryl radical is phenyl, or heterocycle wherein heterocycleis 1-imidazolyl; where the aryl radical or heterocycle may besubstituted up to two times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃, orO—(C₁-C₄)-alkyl, and wherein, on the alkyl groups, one to seven hydrogenatoms may be replaced by fluorine; X is S, SO₂; Y is (CH₂)_(p), where pmay be 0 or 1; R5 is CF₃, or (C₁-C₈)-alkyl, wherein, on,the alkylgroups, one to seven hydrogen atoms may be replaced by fluorine; or R5is phenyl, pyridinyl, where the rings of the phenyl and pyridinyl may besubstituted up to two times by F, Cl, Br, or (C₁-C₈)-alkyl; R9 is F, Cl,Br, (C₁-C₈)-alkyl, wherein, on, the alkyl groups, one to seven hydrogenatoms may be replaced by fluorine; or R9 is (CH₂)_(u)-phenyl, wherephenyl may be substituted up to two times by F, Cl, Br, (C₁-C₈)-alkyl;and their physiologically acceptable salts; provided that when R1, R2,R3 and R4 are all hydrogen, and X—Y—R5 is S-phenyl, then R9 is otherthan phenyl.
 4. A pharmaceutical composition comprising apharmaceutically effective amount of a compound according to claim 1 anda pharmaceutically acceptable carrier.
 5. A method for reducing weightin a mammal in need thereof, comprising administering to such mammal apharmaceutically effective amount of a compound according to claim
 1. 6.A method for reducing weight in a mammal in need thereof, comprisingadministering to such mammal a pharmaceutically effective amount of acomposition according to claim
 4. 7. A method for the prophylaxis ortreatment of obesity in a mammal in need thereof, comprisingadministering to such mammal a pharmaceutically effective amount of acompound according to claim
 1. 8. A method for the prophylaxis ortreatment of obesity in a mammal in need thereof, comprisingadministering to such mammal a pharmaceutically effective amount of acomposition according to claim
 4. 9. A method for the prophylaxis ortreatment of type II diabetes in a mammal in need thereof, comprisingadministering to such mammal a pharmaceutically effective amount of acompound according to claim
 1. 10. A method for the prophylaxis ortreatment of a type II diabetes in a mammal in need thereof, comprisingadministering to such mammal a pharmaceutically effective amount of acomposition according to claim
 4. 11. A method for reducing weight in amammal in need thereof comprising administering to such mammal apharmaceutically effective amount of a compound according to claim 1 incombination with a pharmaceutically effective amount of a furtherpharmacologically active compound suitable for reducing weight inmammals.
 12. A method for the prophylaxis or treatment of obesity in amammal in need thereof comprising administering to such mammal apharmaceutically effective amount of a compound according to claim 1 incombination with a pharmaceutically effective amount of a furtherpharmacologically active compound suitable for reducing weight inmammals.
 13. A method for the prophylaxis or treatment of type IIdiabetes in a mammal in need thereof, comprising administering to suchmammal a pharmaceutically effective amount of a compound according toclaim 1 in combination with a pharmaceutically effective amount of afurther pharmacologically active compound suitable for reducing weightin mammals.
 14. A process for preparing the compounds as claimed inclaim 1, which comprises reacting, according to the formula scheme below

a compound of the formula II via a compound of the formula IV in whichR9 is different from hydrogen and in which the radicals are as definedfor formula I with a sulfur compound of the formula M⁺⁻X—Y—R5 to give acompound of the formula I where X═S and R9 is not hydrogen; and reactingcompounds of the formula I in which X═S and R9 is different fromhydrogen with oxidizing agents to give compounds of the formula I inwhich X═SO or SO₂ and R9 is different from hydrogen; and convertingcompounds of the formula II where R9=H into compounds of the formula Iin which Y is a bond and X═SO or SO₂ and R9 is H, and converting theresulting compounds of the formula I in which X═SO₂ and R9 is H furtherinto compounds in which R9 is not H and has the meanings given above.